The project is to develop novel, safe protease inhibitors for use as oral drugs in the treatment of malaria and Chagas' disease, two parasitic conditions that afflict millions of people worldwide and for which current chemotherapeutic regimens have proven inadequate. Phase I of this effort has already produced lead compounds that are highly effective against animal models of the target diseases. PhaseII will fine-tune the structures of the of the inhibitors to maximize bioavailability and will include dosing, toxicity, and pharmacokinetic studies. 1) Synthesis component: Investigate and map out effects of blocking group modification on the efficacy and bioavailability of Phase I inhibitor, evaluate candidate inhibitors thus derived for stability, purity, ease of synthesis, and feasibility of scale-up, scale up production of selected candidates to kilogram levels for animal studies 2) In vivo safety and efficacy component ( two lead inhibitors per parasite), perform chronic (30-45 day) toxicity studies on selected inhibitors, determine LD 50 values in test animals, determine the pharmacokinetics in two animal models,determine the lifetime of the inhibitors in the blood, determine the optimum dosing to effect cures for Chagas' disease and/or malaria PROPOSED COMMERCIAL APPLICATION This proposal is focused on the development of safe and effective treatments for Chagas' disease and malaria. If successful, the treatments will be submitted for clinical trials through WHO and a pharmaceutical collaborator.